YAP1 作为 EGFR 突变型非小细胞肺癌免疫检查点抑制剂的新型负生物标志物。
YAP1 as a Novel Negative Biomarker of Immune Checkpoint Inhibitors for EGFR-Mutant Non-Small-Cell Lung Cancer.
机构信息
Cancer Institute, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
Medical English Department, College of Basic Medicine, Army Medical University, Chongqing 400038, China.
出版信息
Can Respir J. 2023 Jun 21;2023:4689004. doi: 10.1155/2023/4689004. eCollection 2023.
BACKGROUND
Immune checkpoint inhibitors (ICIs) have become a standard care in non-small-cell lung cancer (NSCLC). However, its application to epidermal growth factor receptor (EGFR)-mutant NSCLC patients is confronted with drug resistance. This study aimed to clarify the potential role of Yes1-associated transcriptional regulator (YAP1) in ICIs treatment for EGFR-mutant NSCLC population.
METHODS
All the clinical data of NSCLC were downloaded from Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) for GSE11969 and GSE72094. Based on YAP1 expression, all the NSCLC patients including the EGFR-mutant and EGFR-wildtype (WT) patients were divided into two groups, YAP1_High and YAP1_Low. Using cBioPortal, genetic alterations were analyzed for identification of immunogenicity in EGFR-mutant NSCLC. MR analysis was used to analyze the hub gene of EGFR. The infiltration of immune cells and the expression of the identified tumor-associated antigens were identified with TIMER. By graph learning-based dimensionality reduction analysis, the immune landscape was visualized. Moreover, survival analysis was performed to verify the predictive value of YAP1 in ICIs treatment for EGFR-mutant NSCLC population using Ren's research data (NCT03513666).
RESULTS
YAP1 was a poor prognostic factor of EGFR-mutant NSCLC population rather than lung adenocarcinoma (LUAD) patients. MR analysis revealed that the EGFR gene regulated YAP1 expression. YAP1 was identified as a hub gene closely associated with immunosuppressive microenvironment and poor prognosis in EGFR-mutant NSCLC population in TCGA LUAD. Tumors with YAP1_High showed an immune-"cold" and immunosuppressive phenotype, whereas those with YAP1_Low demonstrated an immune-"hot" and immunoactive phenotype. More importantly, it was verified that YAP1_High subpopulation had a significantly shorter progression-free survival (PFS) and overall survival (OS) after ICIs treatment in EGFR-mutant NSCLC patients in the clinical trial.
CONCLUSIONS
YAP1 mediates immunosuppressive microenvironment and poor prognosis in EGFR-mutant NSCLC population. YAP1 is a novel negative biomarker of ICIs treatment in EGFR-mutant NSCLC population. . This trial is registered with NCT03513666.
背景
免疫检查点抑制剂（ICIs）已成为非小细胞肺癌（NSCLC）的标准治疗方法。然而，其在表皮生长因子受体（EGFR）突变型 NSCLC 患者中的应用面临着耐药性的问题。本研究旨在阐明 Yes1 相关转录调节剂（YAP1）在 ICIs 治疗 EGFR 突变型 NSCLC 人群中的潜在作用。
方法
从癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）中下载所有 NSCLC 的临床数据，用于 GSE72094 和 GSE11969。根据 YAP1 的表达，将所有 NSCLC 患者（包括 EGFR 突变型和 EGFR 野生型（WT）患者）分为 YAP1_High 和 YAP1_Low 两组。使用 cBioPortal 分析 EGFR 突变型 NSCLC 的遗传改变，以确定其免疫原性。MR 分析用于分析 EGFR 的枢纽基因。使用 TIMER 分析免疫细胞的浸润和鉴定的肿瘤相关抗原的表达。通过基于图学习的降维分析可视化免疫景观。此外，使用 Ren 的研究数据（NCT03513666）进行生存分析，以验证 YAP1 在 ICIs 治疗 EGFR 突变型 NSCLC 人群中的预测价值。
结果
YAP1 是 EGFR 突变型 NSCLC 人群而不是肺腺癌（LUAD）患者的不良预后因素。MR 分析显示 EGFR 基因调控 YAP1 的表达。YAP1 被鉴定为与 EGFR 突变型 NSCLC 人群中免疫抑制微环境和不良预后密切相关的枢纽基因。YAP1_High 肿瘤表现出免疫“冷”和免疫抑制表型，而 YAP1_Low 肿瘤则表现出免疫“热”和免疫激活表型。更重要的是，在临床试验中验证了 EGFR 突变型 NSCLC 患者接受 ICIs 治疗后 YAP1_High 亚群的无进展生存期（PFS）和总生存期（OS）显著缩短。
结论
YAP1 介导 EGFR 突变型 NSCLC 人群中的免疫抑制微环境和不良预后。YAP1 是 EGFR 突变型 NSCLC 人群中 ICIs 治疗的新型负向生物标志物。该试验在 NCT03513666 注册。
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